Mitomycin C is a clinically useful antineoplastic antibiotic compound. This drug is considered the archetypa, example of bioreductive alkylation reagents. The mechanism of action of the mitomycins is poorly understood. In this proposal an integrated approach has been outlined for the elucidation of how both the drug and the receptpr site, DNA, function. Emphasis has been placed on delineating the energetics of key steps in the reaction. The information obtained should be useful in elaborating the pathways of action for the remaining members of this class if medicinal agents. This knowledge may provide the molecular basis for subsequent research in cancer chemotherapy and allow future general drug design to proceed on a less empirical basis. A select series of modified mitomycins are proposed as potential candidates for future pharmacological evaluation. These compounds are expected to have increased activity and decreased toxicity.